Ischemic brain injury from chronic intracranial vaso-occlusive disease is potentially preventable using prophylactic therapies that reduce the risk of recurrent focal ischemia and stroke. Advances in cellular/molecular vascular biology and gene delivery have opened the possibility for angiogenic growth factor therapy with the goal of stimulating the formation of new collateral blood vessels in tissues subject to recurrent ischemia. Such therapies are already being applied with some success to chronic ischemic disorders of the heart and limbs. The development of therapeutic angiogenesis for cerebral vascular disorders has been comparatively slow. Its success, however, would have a major impact on the care and quality of life of patients with cerebral vascular diseases. This application will test the hypothesis that angiogenic growth factors can be used to induce angiogenesis within brain and thereby reduce ischemic brain injury. Aim number 1 will compare the rat brain's angiogenic response to each of three angiogenic factors- fibroblast growth factor-1 (FGF-1), vascular endothelial growth factor (SF/HGF), and scatter factor/hepatocyte growth factor (SF/HGF). Each growth factor will be delivered directly into brain by cell- and adenovirus-based gene delivery and by convection of purified protein. Angiogenic responses will be quantified by computer-assisted morphometric analysis of histologic sections and by noninvasive MRI techniques. Aim number 2 will determine if angiogenic factor delivery produces vessels that are functionally differentiated in a brain-specific manner. Histologic, molecular, and noninvasive MRI approaches will be used to quantify vessel expression of anatomic and biochemical blood-brain barrier properties that normally regulate the brain's microenvironment. Finally, Aim number 3 will determine if angiogenic factor delivery protects rat brain from subsequent transient and permanent middle cerebral artery occlusions. These experiments will establish the feasibility of therapeutic angiogenesis for treating ischemic brain injury and will establish treatment strategies relevant to future clinical applications.